Plectranthus amboinicus (PA) is a traditional Chinese medicine used for coughs, sore throats, and nasal congestion, but also for a range of other problems such as infections, rheumatism, and flatulence. Although the chemical constituents of PA have been extensively studied, its active ingredients for inhibition of AP-1 binding have not been reported.
The transcription factor activator protein-1 (AP-1) regulates expression of various genes by binding to a consensus DNA recognition sequence TGA(C/G)TCA also known as a TPA responsive element (TRE) in the promoter region of target genes. In mammalian cells, AP-1 complexes are mainly formed by members of Fos and Jun-related proteins. AP-1 proteins contain a characteristic amino acid sequence called the bZIP domain. This domain is bipartite; it contains helical conformation and serves as a dimerization interfaces. Interactions between two leucine repeats juxtapose the N-terminal basic regions of two bZIP domains to form a DNA-binding-competent dimer. In vitro studies indicated that stable heterodimer can form between one member of the Fos family and one of Jun class. Jun homodimer can be formed in vitro; yet they are unstable in physiological conditions. Fos homodimer has not been found in normal experimental conditions. In vitro binding and transcription studies indicate that Fos-Jun heterodimer is the predominant active species of AP-1 proteins.
AP-1 activation followed by increased expression of certain genes is a regulator of final steps in a wide range of cellular processes, such as inflammation, stress response, cell differentiation, and tumorigenesis. Therefore, inhibiting the formation of the AP-1-DNA complex is an approach for reducing inflammation and cancer progression. AP-1 activities have been implicated in several autoimmune diseases such as colitis, lupus erythematosus, and rheumatoid arthritis.
Generally, inflammation signaling pathways leads to the activation of several transcription factors including AP-1, which then activate immune cells and induce differentiation of specific cells. A markedly increased expression and high DNA binding activity of AP-1 is found in rheumatoid arthritis synovium. In addition, overexpression of c-fos caused overgrowth of synovial cells and arthritic joint destruction. These observations have led to hypothesize that modulating DNA binding activities of AP-1 may reduce the progression of inflammation in diseases. In fact, the administration of decoy AP-1 oligonucleotides has been shown to reduce collagen-induced arthritis and to attenuate intenstinal inflammation in murine experimental colitis.
Based on these observations, efforts have been made in development of AP-1 inhibitors for inflammatory diseases and cancer. Curcumin, a powerful inhibitor of AP-1 binding activities, has been shown to have anti-cancer activities and can suppress osteoclastogenesis and stimulate osteoclast apoptosis. Momordin I, a strong inhibitor for Jun/Fos dimer formation and the AP-1-DNA binding, can inhibit cancer cell proliferation by inducing apoptosis.
Inflammation has a broad spectrum involvement in many human acute and chronic diseases including allergies, arthritis, gingivitis and most of “-itis” diseases. Inflammation usually starts with tissue injury and subsequent attraction of immune cells to the injured regions to promote healing. Inflammation protects the body, however, it also damages the body if the inflammatory response is unbalanced and outweighs the threat it is dealing with. The anti-inflammatory drugs can be potentially used for autoimmune diseases, rheumatoid arthritis (RA), allergy, cancer, heart disease, and arthrosclerosis. RA is an inflammatory disease mediated by enhanced T-cell activity and is characterized by synovitis and erosion of periarticular bone and joint destruction due to excessive subchondral osteoclastic resorption. Therapeutic management of RA has focused on the development of anti-inflammatory drugs that block cytokine signaling. Current treatments are NSAIDs (nonsteroidal anti-inflammatory drugs), corticosteroids, and DMARDs (Disease Modifying Antirheumatoid Drugs) such as methotrexate, TNF inhibitors, and Actemra (tocilizumab), a humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody.
Inflammation is a response of a tissue to injury. It attracts immune cells for healing via regulation of a variety of different cytokines, which are predominantly activated by the transcription factors of the NF-κB, AP-1, and NFAT, and STAT families. Activator protein-1 (AP-1) is a transcriptional factor that is activated during the cell cycle to promote cell survival, differentiation and adaptive responses. It was recently shown that AP-1 activity is involved in inflammation signaling, suggesting AP-1 may be a new target to intervene inflammation-related diseases.